Mandatory clinical trials needed for implanted medical devices — Oxford study

Organisation: Position: Deadline Date: Location:

MeshMoreWomen have been exposed to unnecessary harm due to poor regulation, most recently for vaginal mesh products for prolapse, and a University of Oxford, study has called for clinical trials to be made mandatory for invasive medical devices, as well as for a registry to be created in response to the mesh scandal.

Cathryn Glazener, emeritus professor at the University of Aberdeen, agreed that tighter regulation was needed to bring device regulation into line with the rigorous scrutiny in place for new drugs.

However, she said a distinction was needed between the use of mesh to treat incontinence, where she said evidence suggested mesh was as effective and safer in the short term than traditional non-mesh operations, and surgery for prolapse, which she said posed greater risks.

Professor Carl Heneghan at Oxford’s Centre for Evidence-Based Medicine, who led the work, said: “Many women have been subjected to great harm because regulatory loopholes allowed mesh devices to be made available in large numbers with no evidence in humans. It is now clear that regulation is not fit for purpose for the riskiest of devices, those that are implanted in the body.

“We now know that women who received mesh implants have been part of a global experiment that in many cases has gone badly wrong.

“It is unacceptable for a health professional to make judgments on what they ‘feel is a good thing to do’. What matters is what does high-quality evidence from randomised trials show, and that is over the long-term – five years at least.”

The paper examined marketing clearance of vaginal mesh devices through the US Food and Drug Administration. In the US, trans-vaginal meshes were initially class II devices, allowing them to be marketed on the basis of equivalence to existing devices. The team found 61 devices that were approved on equivalence claims and said there was no clinical-trial evidence for these devices at the time of approval.

However, many of the devices were significantly different from the original device that had gained approval, with different materials, design and method of surgical implantation. Randomised clinical trials were found to be published an average of five years after device approval, the study found.

“Trans-vaginal mesh products for pelvic organ prolapse have been approved on the basis of weak evidence over the last 20 years,” the authors said.

“When evidence has been forthcoming, it has often emerged too late to inform clinical practice,” they added. “The current systems for ensuring patient safety are inadequate for medical devices.”

The report says concerns have been growing about the serious complications suffered by some women who have had mesh implants and about the introduction of dozens of different devices, most of which have never been assessed in a clinical trial.

In September, it was reported that a vaginal mesh implant made by Johnson & Johnson had been launched without a clinical trial, and then marketed for five years after the company had learned that it had a higher failure rate than its two earlier devices.

The report says the latest paper calls for clinical trials to be made mandatory in order for any implantable device to be marketed. It also calls for a publicly accessible registry of such devices with details of marketing status and linked evidence to the product.

Such a registry would also include details of which devices are given to which patient so if any “shortcomings” are identified then patients can be tracked down.

Stephen Evans, professor of pharmaco-epidemiology at the London School of Hygiene & Tropical Medicine, said: “The absence of good trials for these vaginal meshes, which has been investigated carefully by these authors, shows the problem clearly. Changes in regulation are often driven by lessons learned from very bad situations, such as thalidomide, and the need for change in regard to devices is clear.”


Abstract 1
Introduction: Transvaginal mesh devices are approved in the USA by the Food and Drug Administration (FDA), through the 510(k) system. However, there is uncertainty about the benefit to harm balance of mesh approved for pelvic organ prolapse. We, therefore, assessed the evidence at the time of approval for transvaginal mesh products and the impact of safety studies the FDA mandated in 2012 because of emerging harms.
Methods: We used FDA databases to determine the evidence for approval of transvaginal mesh. To create a ‘family tree’ of device equivalence, we used the 510(k) regulatory approval of the 1985 Mersilene Mesh (Ethicon) and the 1996 ProteGen Sling (Boston Scientific), searched for all subsequently related device approvals, and for the first published randomised trial evidence. We assessed compliance with all FDA 522 orders issued in 2012 requiring postmarketing surveillance studies.
Results: We found 61 devices whose approval ultimately relied on claimed equivalence to the Mersilene Mesh and the ProteGen Sling. We found no clinical trials evidence for these 61 devices at the time of approval. Publication of randomised clinical trials occurred at a median of 5 years after device approval (range 1–14 years). Analysis of 119 FDA 522 orders revealed that in 79 (66%) the manufacturer ceased market distribution of the device, and in 26 (22%) the manufacturer had changed the indication. Only seven studies (six cohorts and new randomised controlled trial) covering 11 orders were recruiting participants (none had reported outcomes).
Conclusions: Transvaginal mesh products for pelvic organ prolapse have been approved on the basis of weak evidence over the last 20 years. Devices have inherited approval status from a few products. A publicly accessible registry of licensed invasive devices, with details of marketing status and linked evidence, should be created and maintained at the time of approval.

Carl J Heneghan, Ben Goldacre, Igho Onakpoya, Jeffrey K Aronson, Tom Jefferson, Annette Pluddemann, Kamal R Mahtani

Abstract 2
Background: There have been no studies of the patterns of post-marketing withdrawals of medicinal products to which adverse reactions have been attributed. We identified medicinal products that were withdrawn because of adverse drug reactions, examined the evidence to support such withdrawals, and explored the pattern of withdrawals across countries.
Methods; We searched PubMed, Google Scholar, the WHO’s database of drugs, the websites of drug regulatory authorities, and textbooks. We included medicinal products withdrawn between 1950 and 2014 and assessed the levels of evidence used in making withdrawal decisions using the criteria of the Oxford Centre for Evidence Based Medicine.
Results: We identified 462 medicinal products that were withdrawn from the market between 1953 and 2013, the most common reason being hepatotoxicity. The supporting evidence in 72 % of cases consisted of anecdotal reports. Only 43 (9.34 %) drugs were withdrawn worldwide and 179 (39 %) were withdrawn in one country only. Withdrawal was significantly less likely in Africa than in other continents (Europe, the Americas, Asia, and Australasia and Oceania). The median interval between the first reported adverse reaction and the year of first withdrawal was 6 years (IQR, 1–15) and the interval did not consistently shorten over time.
Conclusion: There are discrepancies in the patterns of withdrawal of medicinal products from the market when adverse reactions are suspected, and withdrawals are inconsistent across countries. Greater co-ordination among drug regulatory authorities and increased transparency in reporting suspected adverse drug reactions would help improve current decision-making processes.

Igho J Onakpoya, Carl J Heneghan, Jeffrey K Aronson


A BBC Panorama investigation reveals that Ethicon, which markets mesh in the UK under brand name Gynecare TVT, did not update doctors with the extent of risks for its leading mesh device. It also discovered that the product was only tested in 31 women – and on sheep – before being used in patients.

The Independent reports that this comes just over a week after the death of Chrissy Brajcic, the first woman reported to have died from mesh complications, and the publication of a study on vaginal mesh revealing the failures of the regulatory system and “weak evidence” used to support device approval.

The report says the trans-vaginal mesh procedure, which involves implanting a polypropylene netted device into the vaginal wall, is performed on at least 10,000 women in the UK every year to treat prolapse and incontinence. However, mounting evidence of higher risks, severe side effects and insufficient trialling, as well as allegations of corruption and whitewashing, have culminated in what’s been branded “the biggest health scandal since thalidomide”.

Hundreds of thousands of women in the UK, US and Australia are currently involved in lawsuits against mesh producers; at least 800 in the UK are suing the NHS. Ethicon is a wholly-owned subsidiary of multibillion-dollar Johnson and Johnson, one of the main producers of mesh implants and currently the subject of multiple class-action lawsuits.

The company produces “Instructions for Use” (IFU) leaflets to accompany mesh products, designed to explain to doctors how to insert the implants. They also explain the “adverse reactions”, or risks, associated with surgery, to help doctors explain these to patients.

The report says the investigation also revealed that Ethicon’s TVT-Secur implant – sold worldwide, and designed to be the company’s safest mesh product – was launched in 2006 after only being tested on 31 women for five weeks, and some sheep. The product was withdrawn from the market in 2012.

Figures compiled for Panorama by NHS Digital and NHS Wales show that the NHS has implanted more than 130,000 mesh devices in the last decade. In that same period (2006-7 to 2016-17), there have been 6,000 procedures to remove or partially remove the implants. However, the report says, the real number could be much higher: these figures only relate to the NHS in England and Wales, and do not include women who have paid to have the device removed privately, or who received “partial snips” to stop the mesh cutting through the vagina.

Mesh implants for prolapse have led to higher complication rates than mesh implants for incontinence.

A spokesperson for Ethicon said: “While we empathise with those who have experienced complications, the vast majority of women with pelvic mesh see an improvement in their day-to-day lives. All surgical pelvic floor procedures – with and without mesh – come with the risk of developing complications.”

Dr Linda Cardozo, from the Royal College of Obstetricians and Gynaecologists, echoed this, telling Panorama: “You cannot operate without complications occurring in a small minority of cases. You are never aware of complications that may occur years later, and that doesn’t just occur with these tapes and meshes.”

She has previously described a ban as a “retrograde step”, arguing: “If mesh is banned, there will be no more clinical trials. We will go back to how we were a century ago when we couldn’t offer women a range of options.”

But Kath Sansom, founder of prominent anti-TVM campaign group Sling the Mesh, claims that Cardozo speaks with “a heavy bias”. She is quoted in the report as saying: “It is a shame that Linda Cardozo has spoken out on this issue to Panorama without declaring her ties to industry.” Cardozo has previously admitted her ties to Ethicon, and also accepts research monies from Pfizer.

According to Sansom: “Dr Cardozo should have made it very clear that she is a consultant to four industry giants, and a consultant to a UK company that promotes pharmaceutical products and medical devices to the NHS. That means she speaks with a heavy bias.”

The MHRA, the UK medical devices regulator, told Panorama it recognises that some women develop serious complications, but maintains that many women gain benefit from these surgical procedures. It said: “We continue to work closely with NHS England, Nice and professional bodies, and we are all committed to helping address the serious concerns raised by women who have experienced complications.

“Currently, from a regulatory perspective, these devices are acceptably safe when used as intended and as part of an appropriate treatment pathway.”

The report says in October, a cross-party group took a debate to the UK Parliament calling for a suspension pending full inquiry into the scandal, which the government refused.

Later this month, England’s National Institute for Health and Care Excellence (Nice) are expected to recommend banning the mesh devices.

The Guardian report
BMJ Open abstract
BMC Medicine abstract
The Independent report
BBC Panorama programme

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